WO1998032452A1 - Traitement des maladies inflammatoires chroniques par la toxine cm101/gbs - Google Patents

Traitement des maladies inflammatoires chroniques par la toxine cm101/gbs Download PDF

Info

Publication number
WO1998032452A1
WO1998032452A1 PCT/US1998/001852 US9801852W WO9832452A1 WO 1998032452 A1 WO1998032452 A1 WO 1998032452A1 US 9801852 W US9801852 W US 9801852W WO 9832452 A1 WO9832452 A1 WO 9832452A1
Authority
WO
WIPO (PCT)
Prior art keywords
toxin
gbs
patient
gbs toxin
pharmaceutical composition
Prior art date
Application number
PCT/US1998/001852
Other languages
English (en)
Inventor
Carl G. Hellerqvist
Barbara D. Wamil
Original Assignee
Vanderbilt University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vanderbilt University filed Critical Vanderbilt University
Priority to EP98904796A priority Critical patent/EP0981355B1/fr
Priority to DE69816807T priority patent/DE69816807T2/de
Priority to JP53227598A priority patent/JP2001509797A/ja
Priority to AU62588/98A priority patent/AU6258898A/en
Priority to DK98904796T priority patent/DK0981355T3/da
Priority to AT98904796T priority patent/ATE245991T1/de
Publication of WO1998032452A1 publication Critical patent/WO1998032452A1/fr
Priority to HK00105777A priority patent/HK1026372A1/xx

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to the treatment of chronic inflammatory diseases, including rheumatoid arthritis and psoriasis.
  • RA rheumatoid arthritis
  • psoriasis chronic inflammatory diseases such as rheumatoid arthritis (RA) and psoriasis are debilitating diseases affecting millions of people.
  • RA is a systemic, chronic, inflammatory disease affecting approximately 1- 2% of the world's population.
  • the manifestations of RA are usually most severe in the joints.
  • the most frequently affected joints are the proximal interphalangeal and metacarpophalangeal joints in the hands and the metatarsophalangeal joints in the feet.
  • the shoulders, elbows, knees, ankles, and wrists are also common targets of RA.
  • Joints affected by RA ("active" joints) are characteristically tender. Accordingly, RA sufferers often experience pain and impaired mobility. While the severity and progression of RA vary considerably among affected individuals, RA patients as a group have twice the mortality rate of their unaffected counterparts. This decrease in life expectancy appears to be due in part to the side effects of current RA treatments.
  • the synovium of the affected joint becomes enlarged and inflamed. Expansion of the synovium is accompanied by angiogenesis and neovascularization. This, in turn, facilitates infiltration into the area by plasma cells, lymphocytes, and macrophages. As inflammatory cells accumulate within it, the synovium becomes edematous and hyperplastic. Neutrophils infiltrate the synovial fluid and cluster on the surface of the synovium. Fibrin deposition also occurs in the joint space. The synovial fluid increases in volume and turbidity with the accumulation of neutrophils, mononuclear cells and occasional red blood cells.
  • pannus Chronic inflammation causes the synovium to thicken and extend over the articular surface, forming villi which project into the joint space. This aberrant and highly vascularized structure is called a pannus.
  • the pannus invades and erodes the underlying cartilage, with the most active cartilage destruction occurring at the interface between pannus and cartilage.
  • Cartilage destruction is effectuated by collagenase and metallo-proteinases secreted by the inflammatory cells of the pannus. Erosion eventually extends to the subchondral bone, articular capsule and ligaments. Osteoclastic molecules released by the inflammatory cells and synoviocytes allow the synovium to penetrate into the bone and form juxto- articular erosions, subchondral cysts, and osteoporosis.
  • the pannus fills the entire joint space, laying down fibrous bands which bridge the opposing bones. As this fibrous ankylosis becomes calcified, a resulting bony ankylosis forms which fuses the opposing bones and prevents the joint from functioning.
  • RA is an autoimmune disease wherein patients have antinuclear antibodies and antibodies directed at autologous proteins such as immunoglobulin G (IgG), collagen, and cytoskeletal filamentous proteins.
  • Rheumatoid factors are autoantibodies found in serum and synovial fluid which bind to the Fc portion of IgG. RFs have been implicated in the pathogenesis of RA. When RFs bind IgGs, complement-activating immune complexes are formed. Activated complement causes the release of vasoactive and chemotactic substances which attract neutrophils and macrophages to the immune complex.
  • RA RA complexes
  • RFs are synthesized in joints and RFs of the IgG class are self-associating, immune complexes are frequently localized to joints. Nevertheless, immune complexes do circulate in some patients and are thought to cause the extra-articular manifestations of RA such as rheumatoid nodules, reactive amyloidosis and acute vasculitis.
  • RA has autoimmune origins is supported by the finding that injecting avian type II collagen into rats or mice causes them to develop antibodies that recognize the rodent's endogenous collagen.
  • the resulting autoimmune response which is known as "collagen arthritis, " mimics the physiological symptoms of RA such as joint inflammation (Trentham et al., Autoimm nity to type II collagen: an experimental model of arthritis, J. of Experimental Medicine. 146: 857 (1977); Courtenay et al. , Nature. 283: 666).
  • Collagen arthritis is a well established model system for the study of RA (Staines & Wooley, Collagen arthritis-what can it teach us?, British Journal of Rheumatology. 1994, 33: 798 (1994)).
  • the primary method for treating RA is through the administration of drugs which suppress the immune system or reduce inflammation.
  • the two main classes of inflammation inhibitors are corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs).
  • Corticosteroids are not favored RA medications because, although they can achieve dramatic short-term improvements in RA, long-term treatment is not advisable due to serious side effects and diminished effectiveness of the drug.
  • Short-term corticosteroid treatment is also far from ideal because arthritis symptoms rapidly reappear, often with increased severity, after treatment has stopped.
  • corticosteroids such as prednisone can suppress clinical symptoms of RA, the drugs do not prevent RA-mediated joint destruction.
  • typical corticosteroid side effects include: peptic ulcer, hypertension, diabetes mellitus, and glaucoma.
  • NSAIDs such as aspirin, ibuprofen, and indomethacin are frequently prescribed for RA. Although these drugs can reduce swelling in active joints by inhibiting prostaglandin synthesis, their poor penetration of joint spaces necessitates administration of high doses, and such high doses tend to cause gastrointestinal irritation, ulceration, and bleeding. NSAIDs affect prostaglandin- regulate processes not associated with the inflammation process. NSAIDs are also potent renal toxins, and so are also inadequate for treatment of RA.
  • Patients with severe active RA may be treated with immunosuppressants such as cyclophosphamide, methotrexate, and azathioprine. While they can reduce inflammation, these drugs affect the patient's entire immune system and have serious side effects including liver disease, bone marrow suppression, and increased risk of malignancy.
  • immunosuppressants such as cyclophosphamide, methotrexate, and azathioprine. While they can reduce inflammation, these drugs affect the patient's entire immune system and have serious side effects including liver disease, bone marrow suppression, and increased risk of malignancy.
  • RA medications include penicillamine, chloroquine, hydroxy chloroquine, and gold salts. All have potentially serious side effects. D- penicillamine can cause bone marrow suppression, proteinuria, and nephrosis. Deaths resulting from penicillamine treatment have also been reported. Patients treated with hydroxychloroquine or chloroquine must be monitored for signs of irreversible retinal damage. Gold can induce toxic reactions in the form of dermatitis, renal failure or hepatitis, and its efficacy at treating arthritis is questionable.
  • Psoriasis sufferers include approximately 1-3% of the population in the United States and an even higher percentage of Northern Europeans.
  • Psoriasis is a chronic inflammatory skin disease in which the patient's skin exhibits recurrent erythematous plaques. These appear as white or silvery, scaling lesions on the skin, especially in the area of the scalp, elbows, knees, back, and buttocks. The accompanying burning and itching may cause discomfort. In severe forms, severe arthritis or exfoliation develops, as well.
  • the psoriatic lesions exhibit epidermal hyperplasia, infiltration of inflammatory cells, and abnormalities of dermal capillary networks. They are believed to result from epithelial cell hyperproliferation, neovascularization, and, of course, the infiltration of inflammatory cells into the area. Angiogenesis is believed to be necessary to maintain the inflammation and direct neutrophils and lymphocytes into the psoriatic lesion. Additionally, psoriasis patients have autoantibodies directed at the stratum corneum. These autoantibodies are implicated in the pathogenesis of the disease.
  • psoriasis Current treatment for psoriasis includes lubricating creams or oils, keratolytics, and topical corticosteroids.
  • methotrexate may be given, but its high potential for toxicity requires rigidly controlled treatment conditions, including careful monitoring of hematologic, renal, and hepatic function.
  • Treatment for psoriatic arthritis is similar to that for RA, with some exceptions. For example, antimalarials may aggravate the underlying psoriasis.
  • RA and psoriasis are diseases characterized by unregulated angiogenesis.
  • Vascular endothelial growth factor (NEGF) has been implicated in driving such unregulated angiogenesis by stimulating endothelial cells lining nearby microvessels to proliferate and begin the process leading to new blood vessel formation.
  • NEGF vascular endothelial growth factor
  • VEGF receptors are overexpressed by endothelial cells that line the blood vessels supplying the inflammatory reactions leading to these disorders.
  • What is needed is a treatment method for chronic inflammatory diseases such as RA and psoriasis.
  • a compound which inhibits the signs and symptoms of these diseases, and particularly reduces the pain, inflammation, joint swelling, and lesions associated with these diseases.
  • a treatment method, and particularly a compound which is easy to administer and which is nontoxic.
  • One aspect of the present invention is a method for treating patients with chronic inflammatory diseases, such as RA and psoriasis, by administering
  • CM101 a bacterial polysaccharide that is generally nontoxic, to the patient in order to reduce the likelihood of formation of new blood vessels.
  • CM101 may be administered before the onset of RA, when the first symptoms of RA are detected, and/or at later stages in RA progression.
  • CM101 may be administered at various stages of the disease.
  • Another aspect of the present invention is a kit and a method of making a kit having a GBS toxin, preferably CMIOI, in a pharmaceutical composition along with instructions of how to administer the toxin for treatment of chronic inflammatory diseases.
  • CMIOI chronic inflammatory diseases
  • the administration of CMIOI to patients suffering from chronic inflammatory diseases has great utility, specifically in inhibiting the development of RA, reducing joint inflammation in RA patients, and reducing neovascularization in synovial tissues.
  • the method of the present invention has great utility in inhibiting the development of psoriasis and psoriatic arthritis, and particularly in reducing the likelihood of formation of abnormal vasculature which facilitates the inflammatory reactions causing the lesions.
  • Other chronic inflammatory diseases that are characterized by angiogenesis may also be advantageously treated.
  • Figure 1 charts the wrist joint diameters of collagen arthritis-afflicted mice over time.
  • the mice received 20 ⁇ g/kg CM101, 60 ⁇ g/kg CM101, or saline solution.
  • CM101 treatment started on week 4 and continued through week 9. Measurements were taken prior to the start of the experiment (PRE) and at 2, 3, 4, 5, 7, 9 and 11 weeks.
  • Figure 2 charts the foot joint diameters of collagen arthritis-afflicted mice over time.
  • the mice received 20 ⁇ g/kg CM101, 60 ⁇ g/kg CM101, or saline solution.
  • CM101 treatment started on week 4 and continued through week 9. Measurements were taken prior to the start of the experiment (PRE) and at 2, 3, 4, 5, 7, 9, and 11 weeks.
  • Figure 3 charts the elbow joint diameters of collagen arthritis-afflicted mice over time.
  • the mice received 20 ⁇ g/kg CM101, 60 ⁇ g/kg CM101, or saline solution.
  • CM101 treatment started on week 4 and continued through week 9. Measurements were taken prior to the start of the experiment (PRE) and at 2, 3, 4, 5, 7, 9, and 11 weeks.
  • Figure 4 charts the knee joint diameters of collagen arthritis-afflicted mice over time.
  • the mice received 20 ⁇ g/kg CM101, 60 ⁇ g/kg CM101, or saline solution.
  • CMIOI treatment started on week 4 and continued through week 9. Measurements were taken prior to the start of the experiment (PRE) and at 2, 3, 4, 5, 7, 9, and 11 weeks.
  • Figure 5 depicts cross-sections of the knee joint of a normal mouse (A), a collagen arthritis-afflicted mouse (B), and a collagen arthritis-afflicted mouse treated with CMIOI at 60 ⁇ g/kg (C).
  • CM101 a GBS toxin
  • GBS group B ⁇ -hemolytic Streptococcus
  • pathogenic group B 0-hemolytic streptococcus produces a polysaccharide exotoxin.
  • This exotoxin is the putative agent for a condition known as GBS pneumonia or "early-onset disease, " which is characterized by sepsis, granulocytopenia, and respiratory distress, i.e. pulmonary hypertension and proteinaceous pulmonary edema (Hellerqvist, C.G. et al.
  • CM101 has been shown to have toxic effects on sheep experimental models that mimic GBS infant pneumonia (Hellerqvist, C.G. et al. , Studies on group B ⁇ -hemolytic streptococcus I. Isolation and partial characterization of an extra-cellular toxin. , Pediatr. Res.. 12:892-898 (1981)).
  • GBS toxin causes pulmonary hypertension, increased pulmonary vascular permeability, granulocytopenia, and pulmonary sequestration of granulocytes.
  • CM101 has a molecular weight of approximately 300,000 Daltons and comprises N-acetyl-galactosamine, N-acetyl-glucosamine, glucose, galactose, and mannose residues. Carboxylic acid residues are also believed to be an integral part of the molecule. Repeating active epitopes most likely play an important role in the pathophysiological response to CM101 by crosslinking receptors on target endothelium (Hellerqvist, C.G. et al. , Early Results of a Phase I Trial of CMIOI in Cancer Patients. , Proceedings of the American Association of Cancer Research
  • CM101 is purified according to the method taught in International Application No. PCT/US97/17535 incorporated herein by reference.
  • a source for GBS starting material for use in the method of the present invention may be obtained by culturing strains of Group B ⁇ -hemolytic Streptococcus bacteria that have recently infected or are capable of infecting newborn infants. Isolates of such strains may be obtained from the blood or cerebral spinal fluid of infected infants.
  • GBS toxin as used herein is defined as any fraction or component isolated from natural or lysed GBS bacteria, or derived from media supernatants of lysed and/or autoclaved GBS bacteria, and which has a biological activity as evidenced by induction of respiratory distress in the sheep assay (Hellerqvist, C.G. et al. ,
  • GBS toxin a polysaccharide exotoxin from group
  • GBS toxin also means any synthetic polysaccharide with the same structure or function as any GBS-derived molecule with the aforementioned activity.
  • Substantially pure GBS toxin means a preparation in which GBS toxin is greater than 40% pure (e.g. , present in a concentration of at least about 40% by weight), preferably at least approximately 60% pure, more preferably at least approximately 90% pure, and most preferably at least approximately 95% pure.
  • the dosages described herein are for 95 % pure GBS toxin. Dosages of lower purity GBS toxin should be altered accordingly. The purity of GBS toxin is discussed in greater detail in PCT/US97/ 17535.
  • Rheumatoid arthritis or RA as used herein includes any disease that meets the diagnosis criteria set forth by the American Rheumatism Association for rheumatoid arthritis. These criteria are presented in Table 1 which is adapted from Rheumatology. Klippel and Dieppe, eds., Mosby, publ. (1994). RA also includes variants of RA such as juvenile RA, Still's disease, or Felly's syndrome.
  • Treatment of RA as used herein includes the prevention, amelioration, decreased severity, inhibited progression, alleviation or elimination of RA or the symptoms thereof.
  • People who may be treated include persons who have been diagnosed with early stage RA. The criteria for diagnosing RA are listed in Table 1. Persons genetically or environmentally predisposed to developing RA may also be treated, particularly if they have elevated RF levels. RF levels can be measured by agglutination tests such as the latex fixation test or the bentonite tube dilution tests.
  • a mammal is in need of CM101 treatment if the mammal has RA or has a propensity to develop RA.
  • Reduction in the symptoms of RA may be measured by observing the degree of joint swelling or pain, or by radiographic, ultrasound or magnetic resonance imaging of joint morphology. GBS toxin is particularly useful at reducing swelling. Also, heat is a symptom of RA, and the effectiveness of CMIOI can therefore be measured by thermal photographs of joints.
  • CMIOI Monitoring of CMIOI can be achieved by measuring decreases in the level of CD4+ cells. This can be achieved by flow cytometry. Monitoring for an increase in cytokine levels, such as tumor necrosis factor (TNF), 11-8, IL-6, IL-10, and macrophage inflammatory protein (MlP ⁇ ), is also possible. Furthermore, magnetic resonance imaging (MRI) is useful for visualizing vascularization and providing a relative measure of vessel density.
  • CM101 may be administered parenterally, topically, by internal injection of a bolus, by direct injection into affected joints, or by inhalation spray in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous, intradermal, or intraperitoneal injections as well as intravenous, intra-arterial, intramuscular, intrasternal injection or infusion techniques. Parenteral administration is preferable and intravenous administration is most preferable. While a single intravenous administration may last up to 120 minutes, 5 to 60 minutes is the preferable duration range and 5 to 30 minutes is the most preferable duration range.
  • CM101 is administered in doses of at least about l ⁇ g/kg of the patient's body weight, preferably between about 1 and about lOO ⁇ g/kg, more preferably between about 1 and about 50 ⁇ g/kg, most preferably between about 1 and about 25 ⁇ g/kg. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the age, body weight, general health, sex, diet, and severity of the inflammation or the disease of the patient undergoing therapy as well as the time of administration and route of administration of CM101.
  • CM101 may be administered daily, semi- weekly, weekly, semi-monthly or at monthly intervals.
  • the interval will be in the range of one week to one month. Most preferably, the interval will be in the range of 7 days to 2 weeks.
  • the severity of the patient's disease can be taken into account when determining appropriate intervals for CMIOI treatments.
  • the appropriate interval can also be determined by assaying the levels of mature granulocytes in the patient's blood.
  • the level of mature granulocytes is relevant to the timing of CMIOI treatment because CMIOI may cause granulocyte activation and subsequent depletion if administered too frequently. Hence, future CMIOI treatments may be more efficacious if the patient's supply of mature granulocytes has been replenished.
  • One method for monitoring mature granulocyte levels is flow cytometry using the CD69 antigen to detect mature granulocytes.
  • CMIOI treatments may continue over the course of several months, one year, several years, or for the duration of the patient's lifetime.
  • CM101 may be administered on a one-time only basis provided that symptoms of the disease do not reappear.
  • the patient will have at least about 5, 10 or 15 treatments.
  • the CMIOI -mediated reduction in joint swelling may be monitored by external measurements of joint size, degree of tenderness upon palpation, degree of joint mobility, or radiological or other images of joint morphology.
  • the CMlOl-mediated reduction of size, number, and degree of inflammation of psoriatic lesions will be evident upon visual observation.
  • CM101 should be administered in levels sufficient to reduce long-term pain in the body of the patient.
  • CM101 should be administered until the patient experiences pain reduction and additional CM101 fails to effect greater pain amelioration.
  • Intravenous administration could be set up such that the patient can control future dosages of CM101 according to the amount of pain they experience approximately 8 hours after a CM101 treatment.
  • Another aspect of the present invention is an article of manufacture, such as a kit, and a method for making the article of manufacture.
  • the article includes a pharmaceutical composition comprising a GBS toxin, and particularly CM101, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be placed in a suitable container, as is well known in the art.
  • instructions for treatment of patients according to the methods of the present invention are instructions for treatment of patients according to the methods of the present invention.
  • GBS toxin, and especially CMIOI operates as an anti-angiogenic agent which prevents the formation of new blood vessels.
  • CMIOI inhibits angiogenesis by binding dedifferentiated endothelial cells, the cells that are stimulated by hypoxic conditions to form new blood vessels.
  • CMIOI facilitates the binding and opsonization by C3 of endothelial cells, and these cells become the target of inflammatory cells, ultimately leading to the destruction of the endothelial cells.
  • Angiogenesis plays a key role in the pathogenesis of RA because synovial hypoxia induces the release of VEGF which causes the dedifferentiation of endothelial cells and the formation of new blood vessels. Since the formation of these vessels is impeded by CM101 treatment, synovial tissue hyperplasia and lymphocyte infiltration are at least partially inhibited. As a result, the formation of new pannus is minimized, and existing pannus is reduced. These mechanisms are thought to underlie the CM 101 -mediated reduction in joint swelling, acute inflammation, fibrin deposition, and pannus formation demonstrated herein.
  • Angiogenesis also plays a key role in the pathogenesis of psoriasis because it facilitates the infiltration of neutrophils and lymphocytes into the psoriatic lesion. Since the formation of new blood vessels is impeded by CM101 treatment, the formation, maintenance, and enlargement of psoriatic lesions are impaired.
  • RA and psoriasis are both diseases characterized by inflammation. Because inflammation is detrimental to persons suffering from RA or psoriasis, respectively, and there is evidence that CM101 works by stimulating inflammation, it might be expected that CM101 treatment would exacerbate these diseases. Surprisingly, CM101 at least partially reduces the signs and symptoms of inflammatory diseases such as RA and psoriasis.
  • AGM-1470 is an antiangiogenic compound which reduces joint swelling in rats with collagen arthritis (Peacock et al., Angiogenesis inhibition suppresses collagen arthritis, J. Exp. Med.. 175:1135 (1992)).
  • AGM- 1470 is a synthetic analog of fumagillin, a naturally occurring fungal antibiotic derived from Aspergillus fumigatus fresenius (Ingber et al., Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth, Nature. 348:555 (1990)). Since it is not a polysaccharide, AGM-1470 is structurally unrelated to CMIOI .
  • AGM-1470's angiogenic activity is reported to not require induction of the host's immune system (Brem & Folkman, Analysis of experimental antiangiogenic therapy, J. Ped. Sure.. 28:445 (1993)).
  • Another difference between AGM-1470 and CMIOI is that AGM-1470 inhibits both physiological and pathological angiogenesis whereas CMIOI only inhibits pathological angiogenesis.
  • pathological angiogenesis is associated with disease, and physiological angiogenesis occurs under normal, healthy circumstances. Wound healing, the female menstrual cycle, and pregnancy are examples of physiological angiogenesis (Brem & Folkman, Analysis of experimental antiangiogenic therapy, J. Ped.
  • Pathological angiogenesis occurs in diabetic retinopathy, hemangioma, cancer, psoriasis, RA, and osteoarthritis (Folkman et al. , Angiogenic factors, Science. 235:442 (1987); Kimball et al., Meeting report - angiogenesis in pannus formation, Agents & Actions. 34:329 (1991)).
  • AGM-1470 inhibits wound healing (Brem et al., Time dependent suppression of wound healing with the angiogenesis inhibitor, AGM-1470, J. Cell Biol..
  • CM101 does not inhibit placental or endometrial growth. CM101 not only fails to inhibit wound healing, but has actually been shown to facilitate it, as evidenced by a copending application filed concurrently herewith. Therefore, CM101 can be administered to treat RA or psoriasis without causing the undesirable side effects of female infertility or compromised wound healing capacity that would result from AGM- 1470 treatment.
  • a mouse model for RA was utilized to assay the effects of CMIOI on RA (Courtenay et al. , Immunisation against heterologous type II collagen induces arthritis in mice, Nature 283: 666 (1980)).
  • Male mice of the DBA/1 strain received intradermal injections of chicken Type II collagen at 4-6 sites on the back.
  • the injected collagen was prepared as follows: 100 ⁇ g collagen was dissolved in 100ml of 0.1M acetic acid and emulsified in an equal volume of Complete Freund's Adjuvant (0.5 mg/ml M.butyricum).
  • Complete Freund's Adjuvant 0.5 mg/ml M.butyricum
  • Figures 1, 2, 3 & 4 show the diameter measurements of the wrist, foot, elbow and knee joints, respectively, of CMlOl-treated mice and control mice.
  • PRE initial collagen injection
  • All mice had small diameter joints.
  • the joint measurements of CMlOl-treated and control mice continued to be very similar in the weeks following the second round of collagen injections: joint diameters hovered around pre-treatment levels on weeks 2 and 3 and then increased tremendously between weeks 3 and 4.
  • the animals' joints were 35-70% larger than at the start of the experiment.
  • CM101 treatments began in week 4 and continued on a tri- weekly basis until week 9.
  • CMlOl-treated animals exhibited additional reduction in joint size between weeks 9 and 11.
  • week 11 the joint measurements of mice treated with 20 ⁇ g/kg CM101 or 60 ⁇ g/kg CM101 were quite similar ⁇ their joints were significantly smaller than the joints of control mice and had almost returned to their pre- experimentation size.
  • CM101 diminishes pre-existing joint swelling. While the 60 ⁇ g/kg dose reduces swelling more effectively than the 20 ⁇ g/kg dose over short periods of time, the two dosages have similar long-term efficacy. CM101 's therapeutic role in alleviating joint swelling is also supported by results of a similar experiment in which collagen arthritis-afflicted mice were treated with 60 ⁇ g/kg or 240 ⁇ g/kg CM101 from weeks 2 through 9 (data not shown).
  • Example 2 CM101 reduces acute inflammation and pannus formation.
  • CM101 was administered at dosages of 0 ⁇ g/kg, 60 ⁇ g/kg and 240 ⁇ g/kg in saline, and administration occurred three times a week from weeks 2 through 9. Histological sections were made 2 days after the final treatment at week 9.
  • CM101 diminishes the cellular manifestations of RA.
  • articular surfaces are curvilinear in shape and lined by a thin synovial membrane. Just below the synovium lies a thick, even layer of hyaline cartilage (which is darkly stained in these preparations). Under the hyaline cartilage is the subchondral bone.
  • the joint of a mouse with collagen arthritis (Fig. 5B) exhibits flattening of the articular surface, active inflammation in the joint space, synovial hypertrophy and hyperplasia, pannus formation, and mild ankylosis. Destruction of the underlying hyaline cartilage and bone, which was caused by the pannus, is evident.
  • CMlOl-treated mouse Unlike its untreated counterpart, the joint of a CMlOl-treated mouse (Fig. 5C) lacks active inflammation and pannus formation.
  • the hyaline cartilage layer is thick and even.
  • the only morphological signs of arthritis are mild articular flattening, some loss of articular cartilage and subchondral bone, and fibrosis in the area where pannus would otherwise have been.
  • CM101 treatment reduces periarticular inflammation, pannus formation, erosion of cartilage and bone, and ankylosis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Selon une méthode permettant de traiter une maladie inflammatoire chronique telle que la polyarthrite rhumatoïde ou le psoriasis, on traite le patient avec une toxine extraite du streptocoque β-hémolytique du groupe B. La toxine GBS purifiée, ou CM101, peut être administrée au patient en intraveineux, à doses répétées.
PCT/US1998/001852 1997-01-29 1998-01-29 Traitement des maladies inflammatoires chroniques par la toxine cm101/gbs WO1998032452A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP98904796A EP0981355B1 (fr) 1997-01-29 1998-01-29 Traitement des maladies inflammatoires chroniques par la toxine cm101/gbs
DE69816807T DE69816807T2 (de) 1997-01-29 1998-01-29 Behandlung chronischer entzündungskrankheiten mit cm101/gbs-toxin
JP53227598A JP2001509797A (ja) 1997-01-29 1998-01-29 慢性炎症性疾患のｃｍ１０１／ｇｂｓ毒素を用いる治療
AU62588/98A AU6258898A (en) 1997-01-29 1998-01-29 Treatment of chronic inflammatory diseases with cm101/gbs toxin
DK98904796T DK0981355T3 (da) 1997-01-29 1998-01-29 Behandling af kronisk inflammatoriske sygdomme med CM101/GBS toksin
AT98904796T ATE245991T1 (de) 1997-01-29 1998-01-29 Behandlung chronischer entzündungskrankheiten mit cm101/gbs-toxin
HK00105777A HK1026372A1 (en) 1997-01-29 2000-09-14 Treatment of chronic inflammatory diseases with cm101/gbs toxin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/790,989 US6028060A (en) 1997-01-29 1997-01-29 Treatment of chronic inflammatory diseases with CM101/GBS toxin
US08/790,989 1997-01-29

Publications (1)

Publication Number Publication Date
WO1998032452A1 true WO1998032452A1 (fr) 1998-07-30

Family

ID=25152333

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/001852 WO1998032452A1 (fr) 1997-01-29 1998-01-29 Traitement des maladies inflammatoires chroniques par la toxine cm101/gbs

Country Status (12)

Country Link
US (2) US6028060A (fr)
EP (1) EP0981355B1 (fr)
JP (1) JP2001509797A (fr)
CN (1) CN1292759C (fr)
AT (1) ATE245991T1 (fr)
AU (1) AU6258898A (fr)
DE (1) DE69816807T2 (fr)
DK (1) DK0981355T3 (fr)
ES (1) ES2205450T3 (fr)
HK (1) HK1026372A1 (fr)
PT (1) PT981355E (fr)
WO (1) WO1998032452A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6803448B1 (en) 1998-07-22 2004-10-12 Vanderbilt University GBS toxin receptor
US8609614B2 (en) 1998-07-22 2013-12-17 Vanderbilt University GBS toxin receptor compositions and methods of use
US9775896B2 (en) 2004-06-07 2017-10-03 Qu Biologics Inc. Tissue targeted antigenic activation of the immune response to treat cancers
US10130692B2 (en) 2010-07-26 2018-11-20 Qu Biologics Inc. Immunogenic anti-inflammatory compositions
US10251946B2 (en) 2014-05-02 2019-04-09 Qu Biologics Inc. Anti-microbial immunomodulation

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6028060A (en) * 1997-01-29 2000-02-22 Vanderbilt University Treatment of chronic inflammatory diseases with CM101/GBS toxin
US20030175713A1 (en) * 2002-02-15 2003-09-18 Clemens Sorg Method for diagnosis of inflammatory diseases using CALGRANULIN C
EP3487874A1 (fr) 2016-07-20 2019-05-29 Westfälische Wilhelms-Universität Münster Standardisation spécifique d'un complexe de procédés immunologiques pour la quantification de s100a12

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991004048A1 (fr) * 1989-09-25 1991-04-04 Vanderbilt University Agent therapeutique et procede inhibant la vascularisation de tumeurs
WO1997041844A1 (fr) * 1996-05-09 1997-11-13 Alcon Laboratories, Inc. Combinaisons de composes angiostatiques

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS557014A (en) * 1978-06-29 1980-01-18 Chugai Pharmaceut Co Ltd Antitumor agent and its preparation
US4882317A (en) * 1984-05-10 1989-11-21 Merck & Co., Inc. Covalently-modified bacterial polysaccharides, stable covalent conjugates of such polysaccharides and immunogenic proteins with bigeneric spacers and methods of preparing such polysaccharides and conjugataes and of confirming covalency
US5302386A (en) * 1986-04-16 1994-04-12 Brigham And Women's Hospital, Inc. Bacterial antigens, antibodies, vaccines and methods of manufacture
US4895838A (en) * 1988-03-09 1990-01-23 Trustees Of Boston University Method for provoking angiogenesis by administration of angiogenically active oligosaccharides
US5225331A (en) * 1991-04-25 1993-07-06 National Research Council Of Canada Immunoassay for detecting group b streptococcus
US5382514A (en) * 1992-03-31 1995-01-17 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services In vivo angiogenesis assay
DK0666868T4 (da) * 1992-10-28 2006-09-18 Genentech Inc Anvendelse af anti-VEGF-antistoffer til behandling af cancer
US5629327A (en) * 1993-03-01 1997-05-13 Childrens Hospital Medical Center Corp. Methods and compositions for inhibition of angiogenesis
JPH11500119A (ja) * 1995-02-16 1999-01-06 エフ・ホフマン−ラ ロシュ アーゲー インターロイキン１２を用いる脈管形成の阻害
US5811403A (en) * 1996-09-30 1998-09-22 Vanderbilt University Polysaccharide toxin from Group B β-hemolytic Streptococcus (GBS) having improved purity
US6028060A (en) * 1997-01-29 2000-02-22 Vanderbilt University Treatment of chronic inflammatory diseases with CM101/GBS toxin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991004048A1 (fr) * 1989-09-25 1991-04-04 Vanderbilt University Agent therapeutique et procede inhibant la vascularisation de tumeurs
US5010062A (en) * 1989-09-25 1991-04-23 Vanderbilt University Therapeutic agent and method of inhibiting vascularization of tumors
WO1997041844A1 (fr) * 1996-05-09 1997-11-13 Alcon Laboratories, Inc. Combinaisons de composes angiostatiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
C.G. HELLERQVIST ET AL.: "PRELIMINARY RESULTS OF A PHASE I TRIAL OF CM101 IN CANCER PATIENTS.", JOURNAL OF CELLULAR BIOCHEMISTRY, no. SUPPL. 19B, 1995, NEW YORK, N.Y., US, pages 26, XP002054992 *
J. FOLKMAN ET AL.: "ANGIOGENIC FACTORS", SCIENCE, vol. 235, 23 January 1987 (1987-01-23), LANCASTER, PA US, pages 442 - 447, XP002065073 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6803448B1 (en) 1998-07-22 2004-10-12 Vanderbilt University GBS toxin receptor
US7410640B2 (en) 1998-07-22 2008-08-12 Vanderbilt University GBS toxin receptor antibodies
US8609614B2 (en) 1998-07-22 2013-12-17 Vanderbilt University GBS toxin receptor compositions and methods of use
US9775896B2 (en) 2004-06-07 2017-10-03 Qu Biologics Inc. Tissue targeted antigenic activation of the immune response to treat cancers
US10086066B2 (en) 2004-06-07 2018-10-02 Qu Biologics Inc. Tissue targeted antigenic activation of the immune response to treat cancers
US10130692B2 (en) 2010-07-26 2018-11-20 Qu Biologics Inc. Immunogenic anti-inflammatory compositions
US10251946B2 (en) 2014-05-02 2019-04-09 Qu Biologics Inc. Anti-microbial immunomodulation
US10946083B2 (en) 2014-05-02 2021-03-16 Qu Biologies Inc. Anti-microbial immunomodulation
US11819543B2 (en) 2014-05-02 2023-11-21 Qu Biologics Inc. Anti-microbial immunomodulation

Also Published As

Publication number Publication date
HK1026372A1 (en) 2000-12-15
ES2205450T3 (es) 2004-05-01
CN1251997A (zh) 2000-05-03
DK0981355T3 (da) 2003-11-10
US6028060A (en) 2000-02-22
ATE245991T1 (de) 2003-08-15
EP0981355A1 (fr) 2000-03-01
JP2001509797A (ja) 2001-07-24
AU6258898A (en) 1998-08-18
EP0981355B1 (fr) 2003-07-30
DE69816807T2 (de) 2004-04-15
US6476002B1 (en) 2002-11-05
CN1292759C (zh) 2007-01-03
DE69816807D1 (de) 2003-09-04
PT981355E (pt) 2003-12-31

Similar Documents

Publication Publication Date Title
Chenoweth et al. Anaphylatoxin formation during hemodialysis: Effects of different dialyzer membranes
Bridgman et al. Complications during clofibrate treatment of nephrotic-syndrome hyperlipoproteinaemia
WHITE et al. Thrombotic complications of heparin therapy including six cases of heparin-induced skin necrosis
US5650418A (en) Therapeutic lysine salt composition and method of use
O'Riordain et al. Glutamine-supplemented total parenteral nutrition enhances T-lymphocyte response in surgical patients undergoing colorectal resection
US6852708B2 (en) Use of hyaluronic acid and forms to prevent the narrowing of the vascular walls
Puite et al. Whipple's disease
PT1941904E (pt) Anticorpos anti tnf e metotrexato no tratamento de doenças autoimunes
Kubes et al. Rapid mast cell activation causes leukocyte-dependent and-independent permeability alterations
Simkin et al. Free fatty acids in the pancreatitic arthritis syndrome
JP2527749B2 (ja) 移植拒否反応抑制または自己免疫疾患治療用薬学的組成物
US5206223A (en) Method for inhibiting heparanase activity
US6028060A (en) Treatment of chronic inflammatory diseases with CM101/GBS toxin
Galun et al. Pyoderma gangrenosum complicating ulcerative colitis: successful treatment with methylprednisolone pulse therapy and dapsone.
Rose Paracetamol overdose and liver damage.
TAYLOR JR et al. Finger gangrene caused by small artery occlusive disease
EP0891771A1 (fr) Compositions comprenant du lysine et d'ascorbate ou ses dérivés pour le traitement de troubles cardiovasculaires
WO1995026193A1 (fr) Utilisation de differentes formes d'acide hyaluronique pour prevenir la restenose arterielle
Holgate Reflections on the mechanism (s) of action of sodium cromoglycate (Intal) and the role of mast cells in asthma
US20020127289A1 (en) Use of bowman birk inhibitor for the treatment of multiple sclerosis and other autoimmune diseases
RU2155589C2 (ru) Применение 4'-йодо-4'-деоксидоксорубицина для лечения амилоидоза, способ лечения амилоидоза
Tanabe et al. A specific inhibitor of factor Xa, DX-9065a, exerts effective protection against experimental tumor-induced disseminated intravascular coagulation in rats
Graiff et al. Caerulein in the treatment of biliary and renal colic
CA2167044C (fr) Administration par voie orale de quantites efficaces de certaines formes d'acide hyaluronique
JP3006695B2 (ja) 腫瘍壊死因子産生促進剤

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 98802905.7

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 1998 532275

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1998904796

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1998904796

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: CA

WWG Wipo information: grant in national office

Ref document number: 1998904796

Country of ref document: EP